BACKGROUND: At the same time that federal policymakers have enforced restrictive immigration policies, healthcare systems across the USA are developing, and have implemented, interventions aimed at addressing immigration-related stressors faced by immigrant communities. Yet, little is known about the contextual determinants that influence their implementation success. Using the Consolidated Framework for Implementation Research (CFIR), this study identifies factors enabling or challenging the implementation of interventions aimed at mitigating immigration-related stressors in the healthcare context. METHODS: We used a qualitative research design to conduct 38 semi-structured interviews with stakeholders involved in implementation of interventions at 25 healthcare facilities across 5 states with the highest undocumented immigrant populations (California, Texas, New York, Florida, and Illinois). Interviews were conducted from May through August 2018. Constant comparative analysis was used to identify barrier and facilitator themes. Deductive coding was thereafter used to categorize themes according to CFIR domain. RESULTS: Barriers to implementation included perceptions of legal complexity and challenges to adopting such systemic strategies. Facilitators included a national policy climate that had brought immigrant health to the forefront, allowing for leveraging momentum towards institutional change; communication among healthcare personnel; existing community partnerships with immigrant rights and service organizations; and a shared sense of mission centering health equity. Local variation in immigration-related policies (e.g., local law agencies enforcing federal immigration laws) and heterogeneity of local immigrant communities also impacted implementation. Champions and informal leaders were integral to institutional efforts but not sufficient for sustainability. Perceived urgency to act superseded evaluation considerations, with all interventions in initial phases of implementation. Future iterations and evaluations of these interventions are needed to establish best practices and implementation determinants. CONCLUSION: This is the first systematic study describing implementation determinants of immigration-related interventions across health systems. Identifying these determinants provides guidance to other healthcare organizations to effectively strategize and ensure implementation success.